Herpesviruses are important human pathogens, especially problematic for individuals with primary or secondary immunodeficiencies. Severe disseminated herpesvirus infections also occur in newborns and patients with hemopoietic malignancies. The role of human natural killer (NK) cell function in these patients is presently unknown. Lopez showed genetic resistance to herpes simplex virus type I (HSV-1) in the mouse has a similar strain distribution as marrow dependent (M-cell) allogeneic resistance. Since NK cells have many similar properties in common with the M-cell, a natural killer cell assay using HSV-1 infected fibroblasts was developed to study the role of human natural killer cells in virus infection. We plan to study NK activity in patients with recurrent herpesvirus infection and no known immunologic defects. Patients with primary immunodeficiencies associated severe recurrent virus infection particularly selective igA deficiency and Wiskott-Aldrich Syndrome will be compared with immunodeficient patients not as susceptible. Cord blood lymphocytes will also be evaluated for any possible defect in herpes infected NK cell activity which might explain the increased susceptibility observed in newborns. We have observed a deficiency in NK function in an 18 month old boy with neonatal cytomegalovirus associated with decreased lymphokine production. Our studies indicated interferon significantly enhanced his NK activity in vitro. He was treated with interferon and NK activity was followed as a parameter of interferon therapy. His NK activity following interferon therapy rose to the level observed in vitro with interferon. This finding suggests that NK can be followed as a in vitro parameter for interferon therapy and could be used to assay for interferon and interferon-like lymphokines. Furthermore, the observation of low NK activity in patients with no known immunodeficiency defines a cell mediated immune defect in man as yet undescribed and that this is an important area requiring immediate investigation.